Fexofenadine is a second-generation antihistamine drug, without side effects, used in the treatment of allergy symptoms, related to histamine release. Histamine is a mediator of inflammation, antigen response and cellular injury, derived from the decarboxylation of the histidine, by the enzyme L-histidine decarboxylase. Histamine antagonists block release of histamine through inhibition of H1 histamine receptors, especially found on skin, bronchus. The contact of an allergen (a substance that triggers an allergic reaction) with H1 histamine receptors, causes the histamine release, that produce increased capillary permeability, vasodilation, consequently local erythemas, edemas (swellings) and rash. Furthermore, the release of histamine may induce itch, bronchospasm, gastrointestinal motility and secretion of salivary and bronchial glands.
Fexofenadine is the carboxylic acid derivative of Terfenadine of whom is the major metabolite, but without the cardiac toxicity than its parent compound. Fexofenadine does not cross the blood-brain barrier and no sedative or other central nervous system effects were observed. Fexofenadine hydrochloride is a compound of Formula (I)

2-[4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-butyl]phenyl]-2-methylpropanoic acid, which is disclosed in U.S. Pat. No. 4,254,129 and marketed under the trade name of Allegra®. Polymorphism is the property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state. Substances are known which only appear in a single crystal or amorphous form; in addition, however, there are also substances which can form two, three or even more polymorphic crystal modifications. Polymorphs are distinct solids sharing the same molecular formula, having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family.
The morphology of organo-chemical active substances is of great importance to the chemical and pharmaceutical development thereof. One crystalline form may have important advantageous properties compared to other crystalline forms. A process suitable for the synthesis of one crystalline form may offers different advantages to the API (Active Pharmaceutical Ingredients) producers, such as minimum number of chemical steps, the appropriate use of greener solvents and reagents, compounds with a high yield and purity The relevant polymorphism of an organo-chemical substance is always unpredictable in respect of the number of crystal modifications, the stability thereof and their behaviour in a living organism. The different polymorphs of a substance possess different energies of the crystal lattice and, thus, they show different physical properties of the solid state such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc. These differences in morphology and polymorphism may have drastic effects on the flowability of the milled solid (flowability affects the ease with which the material is handled during processing into a pharmaceutical product), development, transport stability and storage stability of individual administration forms, on the ability to produce different administration forms, on their application, on the solubility in polar or non-polar, protic or aprotic solvents, on solubility in aqueous solution, on solubility in the gastric juices, on solubility in blood serum, and finally on bio-availability. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. Other important properties of polymorphic forms relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, Differential Scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by X-Ray Powder Diffraction (XRPD).
The same also applies in respect of the physical and chemical properties of Fexofenadine hydrochloride. It has been found that Fexofenadine hydrochloride may exist in various polymorphs.
WO 00/71124 discloses an amorphous form of Fexofenadine hydrochloride.
WO 95/31437 discloses anhydrous polymorphic forms (forms I and III) and hydrates polymorphic forms (forms II and IV) of Fexofenadine hydrochloride.
EP 1414453 dikloses a polymorph of Fexofenadine hydrochloride.
WO 2005102999 provides crystalline forms of Fexofenadine hydrochloride with different water content (4.4, 7.1 and 8%).
EP 1614681 reports a polymorph of Fexofenadine hydrochloride with a water content of 4.1%, that results difficult to be filter or to separate from the reaction or the crystallization medium.
U.S. Pat. No. 4,254,129 describes a synthesis of Fexofenadine by Friedel-Crafts acylation of an alkyl ester of ,α-dimethylbenzeneacetic acid with 4-halogenbutyryl chloride to give alkyl 4-(4-halogen-1-oxobutyl)-,α-dimethylphenylacetate, that by reaction with ,α-diphenyl-4-piperidinemethanol, subsequently reduction of the cheto to the hydroxy compound and final hydrolysis of the ester group gave the Fexofenadine.
U.S. Pat. No. 6,815,549 describes a process to obtain Fexofenadine, by hydration of 4-{[4-(4-hydroxydiphenylmethyl)-1-piperidinyl]-1-butynyl}-,α-dimethylbenzeneacetic acid and subsequently reduction.
The discovery of novel polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing a pharmaceutical dosage form, or a drug with a targeted release profile, or other desired characteristics, such as flowability and suitable rate of dissolution in aqueous fluid.
Most of the polymorphic forms of Fexofenadine hydrochloride until now known are extremely hygroscopic and/or deliquescent. They absorb water from the moisture already during the operation of separation from the reaction or the crystallization medium, when discharging the filter and/or the dryer. Moreover they may undergo a dissolution/reprecipitation in the moisture, resulting in a change of crystalline phase. This results in extreme technical problems of further processing the Fexofenadine hydrochloride, e.g., in order to produce pharmaceutical compositions. To enable production, usually high technical efforts have to be made and expensive equipment is necessary, like air conditioning to low relative moisture.
Therefore, the preparation of novel stable crystalline forms of Fexofenadine hydrochloride is desirable.
An object of the present invention is to provide a novel crystalline form of Fexofenadine hydrochloride, stable and easily to formulate, an economic and easy process, with few steps for preparing it, pharmaceutical compositions containing it, as well as its use.